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- PDB-1t3r: HIV protease wild-type in complex with TMC114 inhibitor -

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Basic information

Entry
Database: PDB / ID: 1t3r
TitleHIV protease wild-type in complex with TMC114 inhibitor
Componentsprotease RETROPEPSIN
KeywordsHYDROLASE / HIV-1 PROTEASE / DRUG RESISTANCE / THERMODYNAMICS / SUBSTRATE ENVELOPE
Function / homology
Function and homology information


HIV-1 retropepsin / : / retroviral ribonuclease H / exoribonuclease H / : / exoribonuclease H activity / host multivesicular body / DNA integration / RNA-directed DNA polymerase / viral genome integration into host DNA ...HIV-1 retropepsin / : / retroviral ribonuclease H / exoribonuclease H / : / exoribonuclease H activity / host multivesicular body / DNA integration / RNA-directed DNA polymerase / viral genome integration into host DNA / viral penetration into host nucleus / establishment of integrated proviral latency / RNA-directed DNA polymerase activity / Transferases; Transferring phosphorus-containing groups; Nucleotidyltransferases / RNA-DNA hybrid ribonuclease activity / viral nucleocapsid / DNA recombination / Hydrolases; Acting on ester bonds / DNA-directed DNA polymerase / aspartic-type endopeptidase activity / DNA-directed DNA polymerase activity / symbiont entry into host cell / symbiont-mediated suppression of host gene expression / lipid binding / host cell nucleus / structural molecule activity / host cell plasma membrane / virion membrane / proteolysis / DNA binding / RNA binding / zinc ion binding / membrane
Similarity search - Function
Reverse transcriptase connection / Reverse transcriptase connection domain / Reverse transcriptase thumb / Reverse transcriptase thumb domain / Integrase Zinc binding domain / Zinc finger integrase-type profile. / Integrase-like, N-terminal / Integrase DNA binding domain / Integrase, C-terminal domain superfamily, retroviral / Integrase, N-terminal zinc-binding domain ...Reverse transcriptase connection / Reverse transcriptase connection domain / Reverse transcriptase thumb / Reverse transcriptase thumb domain / Integrase Zinc binding domain / Zinc finger integrase-type profile. / Integrase-like, N-terminal / Integrase DNA binding domain / Integrase, C-terminal domain superfamily, retroviral / Integrase, N-terminal zinc-binding domain / Integrase, C-terminal, retroviral / Integrase DNA binding domain profile. / Immunodeficiency lentiviral matrix, N-terminal / gag gene protein p17 (matrix protein) / RNase H / Integrase core domain / Integrase, catalytic core / Integrase catalytic domain profile. / Retroviral nucleocapsid Gag protein p24, C-terminal domain / Gag protein p24 C-terminal domain / Retropepsin-like catalytic domain / Matrix protein, lentiviral and alpha-retroviral, N-terminal / Ribonuclease H domain / RNase H type-1 domain profile. / Reverse transcriptase (RNA-dependent DNA polymerase) / Reverse transcriptase domain / Reverse transcriptase (RT) catalytic domain profile. / Retropepsins / Retroviral aspartyl protease / Aspartyl protease, retroviral-type family profile. / Peptidase A2A, retrovirus, catalytic / Retrovirus capsid, C-terminal / Retroviral matrix protein / Retrovirus capsid, N-terminal / zinc finger / Zinc knuckle / Zinc finger, CCHC-type superfamily / Cathepsin D, subunit A; domain 1 / Acid Proteases / Zinc finger, CCHC-type / Zinc finger CCHC-type profile. / Ribonuclease H superfamily / Aspartic peptidase, active site / Eukaryotic and viral aspartyl proteases active site. / Aspartic peptidase domain superfamily / Ribonuclease H-like superfamily / Reverse transcriptase/Diguanylate cyclase domain / DNA/RNA polymerase superfamily / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
Chem-017 / PHOSPHATE ION / Gag-Pol polyprotein
Similarity search - Component
Biological speciesHuman immunodeficiency virus 1
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.2 Å
AuthorsKing, N.M. / Prabu-Jeyabalan, M. / Nalivaika, E.A. / Wigernick, P.B. / de Bethune, M.P. / Schiffer, C.A.
CitationJournal: J.Med.Chem. / Year: 2005
Title: Discovery and selection of TMC114, a next generation HIV-1 protease inhibitor
Authors: Surleraux, D.L. / Tahri, A. / Verschueren, W.G. / Pille, G.M. / de Kock, H.A. / Jonckers, T.H. / Peeters, A. / De Meyer, S. / Azijn, H. / Pauwels, R. / de Bethune, M.P. / King, N.M. / Prabu- ...Authors: Surleraux, D.L. / Tahri, A. / Verschueren, W.G. / Pille, G.M. / de Kock, H.A. / Jonckers, T.H. / Peeters, A. / De Meyer, S. / Azijn, H. / Pauwels, R. / de Bethune, M.P. / King, N.M. / Prabu-Jeyabalan, M. / Schiffer, C.A. / Wigerinck, P.B.
History
DepositionApr 27, 2004Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 3, 2005Provider: repository / Type: Initial release
Revision 1.1Apr 30, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Non-polymer description / Version format compliance
Revision 1.3Oct 27, 2021Group: Database references / Derived calculations / Structure summary
Category: chem_comp / database_2 ...chem_comp / database_2 / struct_ref_seq_dif / struct_site
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.4Aug 23, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: protease RETROPEPSIN
B: protease RETROPEPSIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)22,6268
Polymers21,6042
Non-polymers1,0236
Water4,666259
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5530 Å2
ΔGint-56 kcal/mol
Surface area9340 Å2
MethodPISA
Unit cell
Length a, b, c (Å)50.746, 57.807, 62.006
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein protease RETROPEPSIN / E.C.3.4.23.16 / HIV-1 PROTEASE


Mass: 10801.763 Da / Num. of mol.: 2 / Mutation: Q7K,L63P
Source method: isolated from a genetically manipulated source
Details: complexed with TMC114 / Source: (gene. exp.) Human immunodeficiency virus 1 / Genus: Lentivirus / Gene: gag-pol / Plasmid: p566 / Production host: Escherichia coli (E. coli) / References: UniProt: P03369, HIV-1 retropepsin
#2: Chemical
ChemComp-PO4 / PHOSPHATE ION / Phosphate


Mass: 94.971 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: PO4
#3: Chemical ChemComp-017 / (3R,3AS,6AR)-HEXAHYDROFURO[2,3-B]FURAN-3-YL(1S,2R)-3-[[(4-AMINOPHENYL)SULFONYL](ISOBUTYL)AMINO]-1-BENZYL-2-HYDROXYPROPYLCARBAMATE / Darunavir / TMC114 / UIC-94017 / Darunavir


Mass: 547.664 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H37N3O7S / Comment: medication, antiretroviral*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 259 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.1 Å3/Da / Density % sol: 41.56 %
Crystal growTemperature: 300 K / Method: vapor diffusion, hanging drop / pH: 6.2
Details: 1 MG/ML PROTEIN; 5:1 LIGAND:PROTEIN; 30% AMSOR; SODIUM CITRATE AND SODIUM PHOSPHATE, pH 6.2, VAPOR DIFFUSION, HANGING DROP, temperature 300K

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Data collection

DiffractionMean temperature: 190 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.9 Å
DetectorDetector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9 Å / Relative weight: 1
ReflectionResolution: 1.2→50 Å / Num. all: 55056 / Num. obs: 55056 / % possible obs: 95.5 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 5.5 % / Rmerge(I) obs: 0.038 / Rsym value: 0.038 / Net I/σ(I): 25
Reflection shellResolution: 1.2→1.24 Å / Rmerge(I) obs: 0.317 / Num. unique all: 4320 / Rsym value: 0.317 / % possible all: 76.2

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Processing

Software
NameVersionClassification
DENZOdata reduction
SCALEPACKdata scaling
AMoREphasing
REFMAC5.1.19refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1F7A

1f7a


Resolution: 1.2→42.26 Å / Cor.coef. Fo:Fc: 0.976 / Cor.coef. Fo:Fc free: 0.965 / SU B: 0.622 / SU ML: 0.028 / Cross valid method: THROUGHOUT / ESU R: 0.04 / ESU R Free: 0.042 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.179 2775 5 %RANDOM
Rwork0.1397 ---
obs0.14 52226 95.52 %-
all-55001 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 15.422 Å2
Baniso -1Baniso -2Baniso -3
1--0.39 Å20 Å20 Å2
2---0.06 Å20 Å2
3---0.45 Å2
Refinement stepCycle: LAST / Resolution: 1.2→42.26 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1496 0 63 259 1818
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0390.0221664
X-RAY DIFFRACTIONr_bond_other_d0.0070.021591
X-RAY DIFFRACTIONr_angle_refined_deg1.5932.0182284
X-RAY DIFFRACTIONr_angle_other_deg0.72233708
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.965215
X-RAY DIFFRACTIONr_dihedral_angle_2_deg
X-RAY DIFFRACTIONr_dihedral_angle_3_deg
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.1490.2270
X-RAY DIFFRACTIONr_gen_planes_refined0.0210.021822
X-RAY DIFFRACTIONr_gen_planes_other0.0280.02301
X-RAY DIFFRACTIONr_nbd_refined0.2440.2285
X-RAY DIFFRACTIONr_nbd_other0.2740.21925
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other0.0950.21088
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2540.2172
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.310.218
X-RAY DIFFRACTIONr_symmetry_vdw_other0.3120.2101
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.3380.249
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_mcbond_it3.2191.51033
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it4.24221690
X-RAY DIFFRACTIONr_scbond_it5.8113631
X-RAY DIFFRACTIONr_scangle_it8.1324.5593
X-RAY DIFFRACTIONr_rigid_bond_restr2.5911664
X-RAY DIFFRACTIONr_sphericity_free16.6453267
X-RAY DIFFRACTIONr_sphericity_bonded9.51131628
LS refinement shellResolution: 1.2→1.232 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.264 146
Rwork0.204 2913

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